Diabetes mellitus (DM) affects more than 25.8 million people in the United States alone, i.e. 8.3% of the population. About 1.9 million people aged 20 years or older were newly diagnosed with diabetes in 2010. An estimated 79 million people aged 20 years or older are believed to have prediabetes, which constitutes 5% of adults aged 20 years or older and 50% of adults aged 65 years or older. National Diabetes Information Clearinghouse, National Diabetes Statistics, 2011.
Much of the morbidity and cost of diabetes management is attributable to long-term diabetes-related complications. For example, diabetes is the leading cause of kidney failure, non-traumatic lower limb amputations and new cases of blindness among adults. Diabetes is also a major cause of heart disease and stroke. After adjusting for population age and sex differences, average medical expenditures among people with diagnosed diabetes were 2.3 times higher than the expected expenditures without diabetes. The cost of diabetes in 2007 was $175 billion, which includes $116 billion in excess medical expenditures and $58 billion in reduced national productivity. Dall, et al., Diabetes Care, 31(3):596-615 (2008).
Based on the current incidence of diabetes and demographics, it has been projected that the number of Americans with diabetic retinopathy will triple to 16 million by 2050, and the major cause of the dramatic expansion in rates of end stage renal disease in this country is due to new cases of diabetic nephropathy. People with diabetes also have a dramatic increase in the risk of heart attack and stroke. It was primarily treatment of these devastating complications that drove the cost of caring for diabetes to $245 billion in 2012, a 45% increase since 2007.
The chronic elevation of blood glucose level associated with DM leads to damage of blood vessels. The resulting problems are grouped under “microvascular disease” (due to damage to small blood vessels) and “macrovascular disease” (due to damage to the arteries). The damage to small blood vessels leads to a microangiopathy, which can cause diabetic retinopathy and/or diabetic nephropathy. Microvascular complications including retinopathy and nephropathy account for the most prevalent and severe morbidity associated with diabetes and are involved in mediating the increased risk of cardio- and cerebrovascular disease as well. Diabetes is also the leading cause of renal insufficiency and end-stage renal disease (ESRD) in the U.S., and the Western world. Although diabetic microvascular complications are clearly associated with the degree of hyperglycemia, not all diabetic individuals with poor glycemic control develop renal or advanced retinal complications. Conversely, some diabetic patients develop severe complications despite well-controlled blood glucose concentrations.
It is distressing that there have been virtually no new biomarkers identified for the early detection of diabetic complications over the past 20-30 years, and the current biomarkers for identifying this “high-risk” subgroup continue to have significant limitations. A first sign for kidney damage is the presence of protein in urine (micro- or macroalbuminuria) which can be assessed by a clinical laboratory test or the latter with a simple dip stick test. The most common test used to date is still serum creatinine while acknowledging its missing accuracy. A limitation of tests relying on microalbuminuria, which occurs when kidney damage is already in place, is that it is only useful for detecting diabetic nephropathy at the asymptomatic stage. Early diagnostic or predictive tests would revolutionize diabetes management, because treatment strategies could be set in place to prevent or delay eventual diabetic nephropathy.
U.S. Pat. No. 6,323,038 discloses a pyridinium compound as a diagnostic reagent for detecting complications associated with diabetes or renal failure. U.S. Publication No. 2011/0079077 discloses urine and serum proteins and their fragments, which alone, or in combination, can be used to diagnose early stage diabetic nephropathy. The current biomarkers (i.e. measures of hyperglycemia) for identifying this “high-risk” subgroup have significant limitations. The Diabetes Control and Complications Trial (DCCT) showed that HbA1c (A1C) alone (i.e., levels of glycated hemoglobin) does not completely determine risk of outcomes. (Beisswenger, et al., Diabetes, 54: 3274-3281 (2005)). The “Natural History of Diabetic Nephropathy Study” has shown that only 9% of the risk of progressive glomerular basement membrane (GBM) thickening in type 1 diabetes is accounted for by the baseline A1C level. The biomarkers for progression of diabetic retinopathy (DR) and diabetic nephropathy (DN), including retinal morphological change or the appearance of albuminuria on regular examinations, are unable to identify those at greatest risk during the long 10-20 year “silent phase” when evolving or incipient damage to the kidney, eyes, and CV system is not clinically apparent (Nathan, et al, New England Journal of Medicine, 353(25): p. 2643-53 (2005)). By the time these markers become positive, substantial pericyte drop-out and avascular capillaries are frequently present in the retina (Ahmed, et al., Biochem Soc Trans, 31(Pt 6):1417-22 (2003), while substantial irreversible kidney damage can be present by the time microalbuminuria occurs (Nathan, et al., New England Journal of Medicine, 353(25):2643-53 (2005)). It is also widely recognized that CV disease may remain silent for many years, in spite of the gradual accumulation of serious and life-threatening lesions (Mauer, et al., J. Renin-Angiotensin-Aldosterone System, 3:262-269 (2002); Almuti, et al., Int. J. of Cardiol., 109(1):7-15 (2006)). In addition, more aggressive treatment for DN with Ace inhibitors (ACEI) and Angiotensin receptor blockers (ARBs) instituted when albuminuria is detected, is unable to slow progression of structural glomerular lesions, as shown by the RASS (Koschinsky, et al., Proc. Natl. Acad. Sci. USA, 94(12):6474-6479 (1997)), suggesting that prevention in a highly susceptible individual is a far superior approach.
As a result of the inability to adequately predict a diabetic patient's risk of developing diabetes related complications, current clinical treatment decisions are made on the premise that all diabetic patients are equally susceptible to complications. This approach is limited, however, since only 50% of patients with type 2 diabetes achieve the recommended A1C treatment goal of <7% in a large population-based study (NHANES) (DCCT/EDIC, JAMA, 287(19):2563-9 (2002)), and the success rates are even lower in type 1 diabetes (Nathan, et al., Diabetes Care, 31(1):173-5 (2008); Holman, et al., New England Journal of Medicine, 359(15):1577-89 (2008)). Reasons for this large-scale failure include the lack of patient specific predictive information, the overwhelming rates of newly discovered diabetes, the massive expense of providing adequate care, the lack of sufficient and adequately trained medical providers, and patient denial of the potential consequences of poor treatment compliance resulting from their lack of accurate individualized predictive information on risk. Diabetes treatments are not only expensive, but some are accompanied by a high-risk of hypoglycemia and drug side effects, as well as the expense and risk of new treatments such as pancreatic transplants and the evolving artificial pancreas. Based on these considerations, it will become increasingly difficult to apply these therapies to all patients with diabetes, without having better information on individual risk and benefit.
Advanced glycation end products (AGEs) and oxidation products (OPs) have been proposed as possible factors for diabetic complications. Until recently, however, knowledge of these products has been limited to the Early Glycation Products (EGPs), several oxidation end products, and a few AGEs. Most prior studies have measured limited numbers of AGEs (Yu, et al. Diabetologia, 49(10):2488-98 (2006); Monnier, et al., Annals of the New York Academy of Sciences, (2008); (Beisswenger, et al., Journal of Clinical Investigation, 92(1):212-7 (1993); Dyer, et al., J. Clin. Invest., 91(6): 2463-9 (1993); Monnier, et al., Annals of the New York Academy of Sciences, 1043:567-581 (2005)), particularly pentosidine and carboxymethyllysine, or have focused on a few end-products that reflect oxidative stress (Yu, et al. Diabetologia, 49(10):2488-98 (2006); Baynes, et al., Free Radical Biology & Medicine., 28(12):1708-16 (2000). A substantial number of these analyses have also been performed as semi quantitative immunoassays, which have generally not been validated against quantitative chemical analyses. Although some of these studies have shown correlations between blood levels of these products and complications (Monnier, et al., Annals of the New York Academy of Sciences, 1043:567-581 (2005)), none have validated their predictive value in large-scale controlled diabetes outcome studies. A recent study by Perkins, et al., PLoS One, 7(4):335655 (2012) measuring the levels of AGEs and oxidative markers in LC/MS/MS concluded that there was no correlation between any of the protein damage adduct residues of plasma protein nor concentration of related free adduct with subsequent early glomerular filtrate rate (GFR) that leads to end stage renal disease.
It is desirable to identify biomarkers that can be used to predict a patient's risk of developing diabetes related kidney disease before the patient exhibits known signs and/or markers of kidney disease or malfunction.
It is an object of the present invention to provide biomarkers useful for determining a diabetic subject's risk of developing kidney disease.
It is also an object of the present invention to provide a method for identifying a subject at risk of developing diabetes related kidney disease.
It is a further object of the present invention to provide a method for identifying a diabetic's risk of eye or cardiovascular disease.